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Neticonazole hydrochloride preparation method

A technology of neconazole hydrochloride and imidazole, which is applied in the field of preparation of neconazole hydrochloride, can solve the problems of high operation risk and non-environmental protection, and achieve the effects of simple operation and post-treatment, content control, and mild reaction conditions

Active Publication Date: 2018-01-09
JIANGSU YUNYANG PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The sodium methylmercaptan used in this route has a foul smell and its decomposition can generate highly toxic sulfur dioxide gas. The thionyl chloride also has a pungent odor and is easily hydrolyzed to generate hydrogen chloride gas. Its operation is highly dangerous and not environmentally friendly.

Method used

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  • Neticonazole hydrochloride preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Embodiment 1: the preparation of formula (3) compound 1-[1-(2-hydroxyphenyl)-2-methanone]-1H imidazole

[0030] Dissolve 30.36g (0.22mol) o-hydroxybenzoic acid in 100mL DMF, add 26.86g (0.2mol) HOBt, 40.95g (0.2mol) DCC in turn, stir at room temperature (about 25-30°C) for 1 hour, then add 13.6g (0.2mol) imidazole, continue to stir at room temperature (at about 25-30°C) for 4 hours, pour the reaction solution into 200mL water, extract twice with 150mL dichloromethane, then successively wash with 5% hydrochloric acid, 1M sodium bicarbonate solution to wash the organic phase. Concentrate the solvent under reduced pressure to obtain a yellow oil, add 80 mL of ethanol, heat to reflux to dissolve the oil, cool down and crystallize for 1 hour, filter, and wash with a small amount of ethanol to obtain 34.55 g of off-white solid product, yield: 91.9%, HPLC purity ( Area normalization method): 98.45%.

Embodiment 2

[0031] Embodiment 2: the preparation of formula (3) compound 1-[1-(2-hydroxyphenyl)-2-methanone]-1H imidazole

[0032] Dissolve 30.36g (0.22mol) o-hydroxybenzoic acid in 100mL DMF, add 26.86g (0.2mol) HOBt, 40.95g (0.2mol) DCC in turn, stir at room temperature (about 25-30°C) for 1 hour, then add 13.6g (0.2mol) imidazole, cooled to 0-10°C and stirred for 5 hours, poured the reaction solution into 200mL water, extracted twice with 150mL dichloromethane, then washed the organic phase with 5% hydrochloric acid and 1M sodium bicarbonate solution successively . Concentrate the solvent under reduced pressure to obtain a yellow oil, add 80 mL of ethanol, heat to reflux to dissolve the oil, cool down and crystallize for 1 hour, filter, and wash with a small amount of ethanol to obtain 31.28 g of off-white solid product, yield: 83.2%, HPLC purity ( Area normalization method): 98.57%.

Embodiment 3

[0033] Embodiment 3: the preparation of formula (3) compound 1-[1-(2-hydroxyphenyl)-2-methanone]-1H imidazole

[0034] Dissolve 30.36g (0.22mol) o-hydroxybenzoic acid in 100mL DMF, add 26.86g (0.2mol) HOBt, 40.95g (0.2mol) DCC in turn, stir at room temperature (about 25-30°C) for 1 hour, then add 13.6g (0.2mol) imidazole, heated to 45-50°C and stirred for 3 hours, poured the reaction liquid into 200mL water, extracted twice with 150mL dichloromethane, then washed the organic phase with 5% hydrochloric acid and 1M sodium bicarbonate solution successively . The solvent was concentrated under reduced pressure to obtain a dark brown oil. Add 80mL of ethanol, heat to reflux to dissolve the oil, cool down and crystallize for 1 hour, filter, wash with a small amount of ethanol to obtain 34.07g of off-white solid product, yield: 90.6%, HPLC purity (area normalization method): 96.53%.

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Abstract

The invention discloses a neticonazole hydrochloride preparation method, which comprises: carrying out an acylation reaction on imidazole and o-hydroxybenzoic acid, carrying out a wittig reaction on the product of the acylation reaction and 1-halogenated dimethyl sulfide, carrying out a reaction on the product of the wittig reaction and 1-halogenated pentane in an inorganic alkali, and salifying the product of the reaction and hydrochloric acid to obtain the neticonazole hydrochloride. According to the present invention, the method can avoid the use of the methanethiol and thionyl chloride, has characteristics of environmental protection, mild reaction condition, simple operation, simple post-treatment and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of neconazole hydrochloride, which belongs to the field of medicine and chemical industry. Background technique [0002] In recent years, the number of cases of clinical fungal infection has been increasing year by year. According to knowledge, the incidence of nosocomial fungal infection has grown from 1.94% in 1987 to 18.84% in 2001. Since the advent of the first antifungal drug, amphotericin B, humans have been fighting fungi for more than 40 years. [0003] At present, the most active antifungal drugs at home and abroad are imidazole antifungal drugs. It can be seen from its chemical structure that the substitution of imidazole at its 1 position is required for the antifungal activity of the drug, and thus various types of imidazole and triazole antifungal drugs can be evolved. The biggest feature of imidazole antifungal drugs is that they are easy to use, have a certain curative effect, and have rela...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/60
Inventor 吴晨晖鲍晓芳朱沉雷董少华
Owner JIANGSU YUNYANG PHARMA GRP
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